Abstract Schizophrenia and other psychotic disorders are highly disabling conditions with poorly understood pathophysiology. One of the central challenges in elucidating mechanisms of psychosis is its remarkable genetic and phenotypic heterogeneity. Taking a `genetics first' approach (i.e., ascertaining patients based on a known, homogeneous genetic etiology) may allow us to overcome the barriers posed by this complexity. 22q11.2 deletion syndrome (Velocardiofacial/DiGeorge syndrome; 22q11DS) is a particularly compelling model, as it represents the greatest known genetic risk factor for psychosis identified to date. As the deletion can be detected very early in development, it offers an extraordinary opportunity for prospective investigation of early biomarkers of psychosis, long before disease-related processes begin to unfold. In the current funding cycle we have elucidated key points of convergence between disturbances in cognition, neural circuitry and gene expression relevant to psychosis in this genetic risk model and in idiopathic psychosis. In this competitive renewal application we plan to continue to prospectively follow a large cohort of youth with 22q11DS (n=90) through the highest risk period for illness onset, and demographically comparable typically developing controls (n=45), in order to establish whether common mechanisms contribute to psychotic symptomatology in 22q11DS and in idiopathic psychosis. Our primary goals (building on our findings from the original funding period) are to elucidate biological pathways and brain biomarkers which may represent convergent mechanisms for disease evolution. Given new discoveries in clinical high risk populations implicating inflammatory and neurohormonal processes in brain changes associated with the development of psychosis, we have added novel measures to assess these domains. In particular, our aims are to: 1) Investigate baseline and progressive abnormalities in structural and functional brain biomarkers, with the prediction that changes in temporal gray matter and thalamo-cortical functional connectivity will predict worsening cognition, social function and increased psychotic symptoms over time; 2) Determine the role of inflammatory mechanisms and stress sensitivity in the evolution of psychotic symptoms, using assays of both peripheral and neural inflammation [i.e., a novel free water diffusion imaging paradigm which is strongly correlated with positron emission tomography (PET) indices of activated microglia] and cortisol at each timepoint; 3) Determine biological pathways associated with psychosis-relevant phenotypes, by investigating upstream regulatory processes of circulating inflammatory markers; and 4) Given the recent discovery that 22q11.2 duplications may be protective against schizophrenia, we will prospectively follow 30 patients with gain of function mutations in the identical locus in order to investigate gene dosage effects on neurobehavioral phenotypes. This work will advance understanding of the genetic and developmental mechanisms by which 22q11.2 haploinsufficiency disrupts brain structure and function and ultimately contributes to disease pathogenesis.